Human activity has resulted in the environmental distribution of many toxic substances, among them the heavy metals that are spread throughout our biosphere. In addition to the acute toxic effects to humans exposed to lead (i.e. in lead paint or in contaminated drinking water) there are more insidious effects of chronic exposure on the development of all organisms. Children exposed to low levels of lead have altered developmental processes, and these children develop symptoms such as hyperactivity, changes in sensory function, and changes in cognitive abilities ("IQ"). Drosophila is a promising model organism to study the effects of lead exposure during development because of (1) the sophisticated understanding of its genetics, and the ease of manipulating its genome; (2) the availability of behavioral and morphological assays sensitive to small effects of very low doses of lead. There is thought to be a great deal of variability in the sensitivity of lead exposure, and both human and Drosophila cells are thought to induce expression of "protective genes" upon exposure to lead. The hypothesis for this proposal is that one can identify some of the "protective genes" that make an organism resistant to the behavioral and developmental effects of lead toxicity using quantitative trait loci (QTL) mapping techniques combined with microarray and sophisticated genetic analyses. To test this hypothesis, Aim 1 is to map lead sensitive QTL by exposing larvae of 90 recombinant inbred Drosophila strains to environmentally relevant doses of lead, and assaying several behavioral and synaptic connection aspects that are affected by lead - such as larval locomotion, adult learning, adult locomotion, adult locomotion combined with ethanol vapor exposure, and the structure of the larval neuromuscular junction. Aim 2 is to perform DNA microarray analyses with labeled mRNA from whole larvae and adult heads from the recombinant inbred lines that show the greatest differences in lead-induced behavioral alterations, as determined in Aim 1. Aim 3 is to up-regulate, by conditional over-expression, or down-regulate, by using existing mutations and RNA interference techniques, the genes that overlap in the assays performed in Aims 1 and 2, and to determine the effects of lead on cognition, locomotion and synaptic function of these genetically altered flies. Results of these studies will identify candidates for the most important genes that are altered during lead exposure in humans, and could well lead to bioassays or treatments for heavy metal exposure at or below NOAEL and LOAEL values.